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  • 1
    Online Resource
    Online Resource
    Quiescence of Memory CD8+ T Cells Is Mediated by Regulatory T Cells through Inhibitory Receptor CTLA-4
    Elsevier BV ; 2015
    In:  Immunity Vol. 42, No. 6 ( 2015-06), p. 1116-1129
    Details
    In: Immunity, Elsevier BV, Vol. 42, No. 6 ( 2015-06), p. 1116-1129
    Type of Medium: Online Resource
    ISSN: 1074-7613
    URL: Article
    DOI: 10.1016/j.immuni.2015.05.023
    RVK:
    XA 48754.8
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 2001966-X
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  • 2
    Online Resource
    Online Resource
    Programming of CD8 T Cell Quantity and Polyfunctionality by Direct IL-1 Signals
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 201, No. 12 ( 2018-12-15), p. 3641-3650
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 201, No. 12 ( 2018-12-15), p. 3641-3650
    Abstract: IL-1, generally considered an amplifier of adaptive immune responses, has been proposed for use as adjuvant during immunization with weak immunogens. However, its effects on memory T cell function remain largely undefined. Using the murine model of acute viral infection, in this paper, we show that in addition to augmenting the size of the Ag-specific pool, IL-1 signals act directly on CD8 T cells to promote the quality of effector and memory responses. Ablation of IL-1R1 or MyD88 signaling in T cells led to functional impairment; both the ability to produce multiple cytokines on a per cell basis (polyfunctionality) and the potential for recall proliferation in response to antigenic restimulation were compromised. IL-1 supplementation during priming augmented the expansion of Ag-specific CD8 T cells through the MyD88–IRAK1/4 axis, resulting in a larger memory pool capable of robust secondary expansion in response to rechallange. Together, these findings demonstrate a critical role of the IL-1–MyD88 axis in programming the quantity and quality of memory CD8 T cell responses and support the notion that IL-1 supplementation may be exploited to enhance adoptive T cell therapies against cancers and chronic infections.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1800906
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Dicer Regulates the Balance of Short-Lived Effector and Long-Lived Memory CD8 T Cell Lineages
    Public Library of Science (PLoS) ; 2016
    In:  PLOS ONE Vol. 11, No. 9 ( 2016-9-14), p. e0162674-
    Details
    In: PLOS ONE, Public Library of Science (PLoS), Vol. 11, No. 9 ( 2016-9-14), p. e0162674-
    Type of Medium: Online Resource
    ISSN: 1932-6203
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1371/journal.pone.0162674
    DOI: 10.1371/journal.pone.0162674.g001
    DOI: 10.1371/journal.pone.0162674.g002
    DOI: 10.1371/journal.pone.0162674.g003
    DOI: 10.1371/journal.pone.0162674.g004
    DOI: 10.1371/journal.pone.0162674.g005
    DOI: 10.1371/journal.pone.0162674.s001
    DOI: 10.1371/journal.pone.0162674.s002
    DOI: 10.1371/journal.pone.0162674.s003
    DOI: 10.1371/journal.pone.0162674.s004
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2016
    detail.hit.zdb_id: 2267670-3
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  • 4
    Online Resource
    Online Resource
    Autocrine and paracrine IL-2 signals collaborate to regulate distinct phases of CD8 T cell memory
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 133.1-133.1
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 133.1-133.1
    Abstract: Proliferation is a defining feature of clonal cytotoxic T lymphocyte (CTL) responses upon activation. However, how proliferative events during primary expansion relate to divergent CD8 T cell fate outcomes remains poorly defined. Emerging evidence from our laboratory and others in the field suggest that death-fated effectors undergo more pronounced proliferation compared to memory-fated cells during antigen-driven T cell expansion. Adoptive transfer of activated CD8 T cell-subsets, purified based on their extent of proliferation, showed that in vivo differentiation of CD8 T cells and memory fate are linked to proliferation. We found that the less-divided effector CTL subset preferentially contributed to the central memory lineage. Interestingly, these less-divided memory precursor cells were also programmed to produce more IL-2 compared to their more-divided terminal effector counterparts. How do memory-fated cells that make their own IL-2 (a pro-proliferative cytokine) proliferate less and how does this make them better fit for the long-lived memory lineage? To answer this question, we generated CD8 T cells that could be conditionally ablated for il2. We ablated IL-2 specifically in antigen-specific CD8 T cells, during distinct phases of effector and memory differentiation. Our data showed that while paracrine IL-2 is critical for driving the early in vivo proliferative burst, the programmed life-long autochthonous IL-2 in memory-fated cells was necessary for antigen-independent maintenance, and robust secondary expansion of memory cells. Thus, autocrine and paracrine IL-2 signals collaborate during distinct stages of T cell differentiation to direct diverse CTL lineages through effects on proliferation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.133.1
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Signaling through PD-1 on CD8 T cells is critical for antigen-independent maintenance of immune memory
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 129.6-129.6
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 129.6-129.6
    Abstract: PD-1 is highly expressed on CD8 T cells during activation, both in acute and chronic viral infections. Inhibitory signaling in cytotoxic T cells through the PD-1 axis is well characterized during chronic infections and has led to the development of potent blockade therapies that restore function to otherwise exhausted CD8 T cells. However, the functional significance of transiently increased PD-1 expression on CD8 T cells early after activation and its rapid down-regulation following clearance of antigen during acute infections, remains to be characterized. The enigma is – expression of PD-1 (an immunological brake) during activation temporally coincides with rapid proliferation and production of copious amounts of signature effector cytokines (IFN-γ and TNF-α). We generated PD-1−/− antigen-specific CD8 T cells to study its cell-intrinsic role during acute infection with LCMV. Unexpectedly, PD-1−/− cells did not exhibit increased proliferation early during infection, or enhanced accumulation at the peak of expansion. PD-1−/− CD8 T cells were also unaltered in their polyfunctionality and granzyme B expression. Despite robust effector properties, PD-1−/− CD8 T cells underwent precipitous contraction, leading to near ablation of the memory pool. Mechanistically, in vivo analysis of PD-1−/− memory cells showed a severe defect in antigen-independent homeostatic proliferation due to decreased sensitivity to IL-2, −7, and −15 signals, without evident change in the expression of common gamma-chain cytokine receptors. These studies demonstrate a previously unrecognized role of PD-1 signaling in programming of memory CD8 T cell maintenance and could make it a novel target for manipulating vaccine-induced memory T cell longevity.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.129.6
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    PD-1 signals instruct a critical metabolic switch for maintenance of T cell memory
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 151.24-151.24
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 151.24-151.24
    Abstract: PD-1 is highly expressed on CD8 T cells during activation, both in acute and chronic viral infections. Inhibitory signaling in cytotoxic T cells through the PD-1 axis is well characterized during chronic infections and has led to the development of clinical checkpoint blockade therapies that restore function to otherwise exhausted CD8 T cells. However, the functional significance of transient PD-1 expression on T cells early after activation during acute infections remains yet to be characterized. It is paradoxical that expression of PD-1 (an inhibitory receptor) during activation temporally coincides with rapid proliferation and production of copious amounts of signature effector cytokines (IFN-γ and TNF-α). Our studies using PD-1−/−antigen-specific CD8 T cells revealed an unexpected lack of an inhibitory role for PD-1 early during priming - PD-1−/−T cells exhibited similar proliferation, accumulation, cytotoxicity and polyfunctionality compared to WT T cells. Surprisingly, PD-1−/−T cells underwent precipitous contraction, leading to near ablation of the memory pool. Mechanistically, PD-1−/−memory Tcells showed a severe defect in antigen-independent homeostatic proliferation in vivo, despite identical expression of common gamma-chain cytokine receptors as WT T cells. Notably, PD-1−/−memory T cells failed to optimally switch the critical utilization of glucose to fatty acid as an energy source, which impaired their homeostatic maintenance and resulted in attrition. These findings show a previously unrecognized role of PD-1 signaling in programming a metabolic switch that is critical for the maintenance of memory CD8 T cells and could make it a novel target for manipulating vaccine-induced memory T cell longevity.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.151.24
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    PD-1 Signals are Critical for Homeostatic Maintenance of Memory CD8 T Cells
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 81.5-81.5
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 81.5-81.5
    Abstract: Inhibitory signaling in dysfunctional CD8 T cells through the PD-1 axis is well established in chronic viral infections and cancers. PD-1 is also transiently induced to high levels during priming of acute infections and immunizations, yet its impact on the development of long-lived antigen-independent T cell memory remains unclear. Here we show that in addition to its expected role in restraining clonal expansion, PD-1 expression on antigen-specific CD8 T cells during priming and activation is critically required for the development of a durable CD8 T cell memory pool after antigen clearance. Loss of T cell-specific PD-1 signaling led to increased contraction and a striking defect in antigen-independent renewal of memory CD8 T cells in response to homeostatic cytokine signals, thus resulting in attrition and near ablation of the memory pool over time. Notably, in the setting of PD-1 checkpoint blockade immunotherapy of chronic viral infection, while the exhausted CTLs expectedly regained function, the pre-existing pool of resting functional memory cells established in response to a previously administered vaccine underwent attrition. Metabolically, PD-1 signals were necessary for regulating the critical balance of anabolic glycolysis and fatty acid oxidation programs through mTOR to meet the bioenergetics needs of quiescent memory. These studies define PD-1 as a key metabolic regulator of protective T cell immunity, and have potential clinical implications for pre-existing T cell memory to prior infections and vaccinations during PD-1 checkpoint-blockade immunotherapy in cancer.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.81.5
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 8
    Online Resource
    Online Resource
    Early CD8 T-cell memory precursors and terminal effectors exhibit equipotent in vivo degranulation
    Springer Science and Business Media LLC ; 2015
    In:  Cellular & Molecular Immunology Vol. 12, No. 4 ( 2015-7), p. 400-408
    Details
    In: Cellular & Molecular Immunology, Springer Science and Business Media LLC, Vol. 12, No. 4 ( 2015-7), p. 400-408
    Type of Medium: Online Resource
    ISSN: 1672-7681 , 2042-0226
    URL: Article
    DOI: 10.1038/cmi.2014.48
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 2219471-X
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  • 9
    Online Resource
    Online Resource
    Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Translational Medicine Vol. 13, No. 615 ( 2021-10-13)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 13, No. 615 ( 2021-10-13)
    Abstract: Inhibitory signaling in dysfunctional CD8 T cells through the programmed cell death 1 (PD-1) axis is well established in chronic viral infections and cancers. PD-1 is also transiently induced to high concentrations during priming of acute infections and immunizations, yet its impact on the development of long-lived antigen-independent T cell memory remains unclear. In addition to its expected role in restraining clonal effector expansion, here, we show that PD-1 expression on antigen-specific CD8 T cells is required for the development of a durable CD8 T cell memory pool after antigen clearance. Loss of T cell–specific PD-1 signaling led to increased contraction and a defect in antigen-independent renewal of memory CD8 T cells in response to homeostatic cytokine signals, thus resulting in attrition of the memory pool over time. Whereas exhausted CD8 T cells regain function after PD-1 checkpoint blockade during chronic viral infection, the preexisting pool of resting functional bystander memory CD8 T cells established in response to a previously administered immunogen decreased. Metabolically, PD-1 signals were necessary for regulating the critical balance of mTOR-dependent anabolic glycolysis and fatty acid oxidation programs to meet the bioenergetic needs of quiescent CD8 T cell memory. These results define PD-1 as a key metabolic regulator of protective T cell immunity. Furthermore, these results have potential clinical implications for preexisting CD8 T cell memory during PD-1 checkpoint blockade therapy.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.aba6006
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 10
    Online Resource
    Online Resource
    Vitamin D regulates CD8 T cell expansion and immune memory to infections (IRM4P.502)
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 192, No. 1_Supplement ( 2014-05-01), p. 61.9-61.9
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 192, No. 1_Supplement ( 2014-05-01), p. 61.9-61.9
    Abstract: Epidemiological studies implicate a potential role of vitamin D in modulating immune responses to infections and vaccines. In this study we analyzed the contribution of vitamin D signals to the development and maintenance of antigen-specific memory CD8 T cell responses during a viral infection. Using the vitamin D receptor (VDR)-deficient murine model, we found that lack of vitamin D signals resulted in a dysregulated CD8 T cell expansion program, which was largely attributable to cell-extrinsic effects. Investigation of events proximal to TCR activation demonstrated a delayed yet sustained priming of antigen-specific CD8 T cells in the absence of vitamin D signals. In spite of a larger ensuing effector CD8 T cell pool generated in the absence of vitamin D signals, the final memory pool was smaller. Interestingly, within both effector and memory CD8 T cell pools, we observed a bias towards CD8 T cells specific for immunodominant determinants, resulting in a restricted repertoire of antigen-specific CD8 T cells in the absence of vitamin D signals. Collectively, these studies delineate a critical role of vitamin D in regulating the quantity and quality of adaptive T cell immunity. Importantly, our studies have direct impact on the efficacy of vaccines, owing to disparate nutritional states of vitamin D that are currently seen cross-sectionally around the world.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.192.Supp.61.9
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
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